ABSTRACT Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BC) with no targeted therapy options yet available and relying primarily on conventional chemotherapy. However, TNBC patients often develop chemotherapy resistance during the course of treatment. Identification of novel ?druggable? mediators of chemotherapy resistance in TNBC has potential to improve the treatment of chemotherapy-resistant TNBCs. Recent studies revealed a high rate of chromosomal instability, aberrant NF B signaling, mutations in DNA repair enzymes, altered expression of drug transporter proteins, greater drug detoxification and imbalance of genes regulating apoptosis as chemotherapy resistance mechanisms in TNBC. In addition to these cell intrinsic mechanisms, the extracellular matrix (ECM) being a major component of tumor microenvironment may play a multifaceted role in chemotherapy resistance in TNBC. However, ECM has been studied mostly in the context of metastasis rather than drug resistance in breast cancer. This proposal is based on our recent findings that hypoxia-induced lysyl oxidase (LOX: an ECM re-modeler) promotes resistance to chemotherapeutic agents (anthracyclines and taxanes) in TNBC by hyperactivating integrin signaling. In addition, inhibition of LOX expression or its activity synergizes with chemotherapeutic agents and overcomes therapy resistance in TNBCs. Furthermore, in addition to the known matrix re-modeling function of LOX (mature form) outside the cell, we discovered nuclear localization of LOX (pre pro-protein LOX form) potentially regulating transcription. Aim 1 is to elucidate the mechanism of integrin signaling regulation by LOX and to investigate its contribution to chemoresistance in TNBCs both in vitro and in vivo. Aim 2 is to perform a high-throughput screen (HTS) of a diversified compound library using a LOX activity assay and an in silico screen using a pharmacophore model to identify novel inhibitors of LOX. Proteolysis targeting chimeric molecule (PROTAC) approach will then be used to generate LOX-degrading compounds. The potential of different types of LOX inhibitors as sensitizers to different chemotherapeutic agents will be investigated. Aim 3 is to test LOX inhibitors in combination with chemotherapeutic agents in transcriptionally-characterized patient derived xenograft (PDX) models representing tumor heterogeneity and organoids derived from the PDXs. The ultimate goal of this study is to develop a combination of chemotherapeutic agents with potent and selective LOX inhibitors that will pave the way towards improving the efficacy of chemotherapy and survival of TNBC patients.